Pharmaceutical Research (2022) 39:3175–3184

https://doi.org/10.1007/s11095-022-03196-z

RESEARCH PAPER

Improving the Effectiveness of the Conical Screen Mill as a Dry-Coating

Process at Lab and Manufacturing Scale
Maxx Capece1 · Jeffery Larson1

Received: 16 November 2021 / Accepted: 10 February 2022 / Published online: 17 February 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022

Abstract
The conical screen mill (comill) is investigated as a dry-coating process for flowability and bulk density enhancement of
pharmaceutical powders. In this study, the effectiveness of the comill is improved by using modified screens with reduced
open area. In comparison to the screens provided by the comill manufacturer, the modified screens increase mean residence
time of the process and improve the extent of flowability and bulk density enhancement. The effectiveness of the comill as
a dry-coating process is demonstrated using Avicel PH 105, a fine grade of microcrystalline cellulose, as a model cohesive
powder. The process is evaluated thoroughly using a lab scale comill and scalability is demonstrated using a manufacturing
scale model. The use of the modified screens is also compared against the so-called “multi-pass” approach in which mate-
rial is passed through the comill, collected, and passed through once or several times. While the “multi-pass” approach is
offered as a simple method to increase mean residence time and to improve process effectiveness, the use of the modified
screens is shown to be the superior approach. Due to the ubiquitous use of the comill and the improvement in effectiveness
attained in this study, dry-coating is shown to be a practical and readily implemented process for the pharmaceutical industry.

Keywords Comilling · Dry-coating · Flowability enhancement · Bulk density enhancement

Introduction among other applications [17–25]. The comill uses a spin-

The use of dry-coating processes to coat fine particles with
glidants is a promising method to improve the bulk prop-
erties of cohesive powders [1–4]. Among the many appli-
cations of dry-coating, improvement to bulk density and
flowability of cohesive powders is of particular importance
in tablet and capsule manufacturing [5–9]. Bulk density and
flowability are important powder properties that can sig-
nificantly affect formulation and process development [10,
11]. While many types of processing equipment exist for
the purpose of dry-coating [1, 2, 12–16], the conical screen
mill (comill) has particular relevance to the pharmaceutical
industry due to its ubiquitous use albeit as a size reduction
or sifting/de-lumping process.
Many studies have shown comilling as a potentially useful
dry-coating process to improve bulk density and flowability
* Maxx Capece
maxx.capece@abbvie.com
1
Drug Product Development, Research and Development,
AbbVie Inc., 1 N. Waukegan Road, North Chicago,
IL 60064, USA
ning impeller which imparts shear to deagglomerate, dis-
perse, and coat glidant onto fine and cohesive powders in an
exceptionally simple process as shown in Fig. 1. Due to the
design of the comill as a continuous process, the effective-
ness as a dry-coating process can unfortunately be limited by
the short residence time of the powder in the impeller zone.
To increase the residence time and to improve the process,
studies use a “multi-pass” or “recycle” approach in which
the material is passed through the comill, collected, and
passed through once or several more times [21–25]. While
this approach is straightforward, it is also inefficient and may
not be desired in a manufacturing setting.
In our previous study [26], the effectiveness of the comill
as a dry-coating process was significantly improved at the
lab scale by using modified screens with reduced open area
as shown in Fig. 2. In comparison to the manufacturer’s
screen which was designed for size reduction, the modi-
fied screens with low open area reduce the mass through-
put while also forcing powder to pass through the impeller
zone before discharging at the bottom of the screen. This
simple modification to the screen increases the residence
time of the process allowing for the most enhancement in

13
Vol.:(0123456789)
3176
Fig. 1.  Pharmaceutical Research Special Issue: Pharmaceutical Parti-
cle and Crystal Engineering. Depiction of a comill used for the dry-
coating of glidant.
Fig. 2.  Pharmaceutical Research Special Issue: Pharmaceutical Par-
ticle and Crystal Engineering. Comparison between manufacturer’s
screen and modified screen with low open area. Screens for the Comil
197 are depicted.
flowability and bulk density. While this study showed that
the comill can be repurposed from a size reduction process
and be developed as a dry-coating process with a switch of
the screen, several issues were not addressed. Primarily, the
effect of impeller speed was not evaluated for the modified
screens and no attempt to dry-coat using a manufacturing
scale comill was attempted. In addition, no comparison was
made against the “multi-pass” method which is regarded
13
Pharmaceutical Research (2022) 39:3175–3184
as the leading approach to improve the effectiveness of the
comill as a dry-coating process.
In this study, the comill as a dry-coating process using
the modified screen with reduced open area is investigated
comprehensively. As an extension to our previous study, the
effect of impeller speed on the mean residence time and the
extent of flowability enhancement is evaluated for the modi-
fied screens. In addition, the use of the modified screens
is compared against the “multi-pass” approach to evaluate
which method is more effective. As a major novelty, a manu-
facturing scale comill (Comil 197) is investigated and com-
pared against the lab scale model (Comil U3). It is the pur-
pose of this study to show that the comill can be developed
and used as an effective dry-coating process at the larger
scale using the modified screens with reduced open area.
Accordingly, dry-coating for the purpose of bulk density and
flowability improvement can be shown to be a practical and
scalable process for pharmaceutical manufacturing.
Materials and Methods
Materials
Avicel PH 105 grade of microcrystalline cellulose was pur-
chased from DuPont, USA. Pharmaceutical grade nano-sized
silica, Aerosil R972, was purchased from Evonik, USA, and
was used as a glidant.
Bin Blending
Avicel PH 105 and Aerosil R972 were blended in a 10 L bin
rotated at 15 RPM using a PK Blend Master Model B Lab
Blender. The bin has a 10 L “working volume” and a 14.5 L
total volume. Each batch size of 3.25 kg was blended for 60
minutes. Blends prepared by this method were used as the
feed material for all comilling experiments.
LabRAM Blending
Avicel PH 105 and Aerosil R972 were blended using a high
intensity vibrational mixer called the Laboratory Acous-
tic Mixer (LabRAM, Resodyn, USA). Materials were first
weighed and then dispensed into a cylindrical glass jar with
a height of 10 cm and an inner diameter of 9 cm weighing
350 g loaded with 50 g of powder. The powder was blended
for 5 min at 75 g and 60 Hz which respectively refers to the
acceleration and frequency of vibration of the jar.
Comilling
An experimental set-up as shown in Fig. 3 was used for
comilling. A lab scale U3 model and a manufacturing scale
Pharmaceutical Research (2022) 39:3175–3184 3177

Table 2.  Properties of the 1397 μm Comil Screens

Comil Screen Holes (#) Open Area (%)

U3 Manufacturer 815 29
75% Blocked 137 4.9
90% Blocked 87 1.9
197 Manufacturer 3300 29
75% Blocked 490 4.3
90% Blocked 186 1.6

Fig. 3.  Pharmaceutical Research Special Issue: Pharmaceutical
Particle and Crystal Engineering. Experimental set-up for comilling
using the U3 model (left) and the 197 model (right).
197 model Quadro Comil (Quadro Engineering, USA) with
a square-shaped impeller were used for all experiments.
Round hole screens with 1397 μm diameter openings were
used. Additional properties of the comills and screens used
are listed in Table 1 and Table 2. The blended feed material
from the 10 L bin was allowed to flow into the comill unas-
sisted except by gravity. The U3 was ran at a predetermined
impeller speed, depending on the throughput, to collect
approximately 400 g of product. Similarly, approximately
750 g of product was collected per batch for the 197. The
entirety of the material collected was used for analysis. To
calculate the mass throughout, the processing time and the
exact product mass was recorded. Each comill experiment
was conducted in duplicate.
Determination of Mean Residence Time
Mean residence time of powder in the impeller zone was
calculated by measuring the mass hold-up mH and the mass
throughput ṁ as required by Eq. (1).
Table 1.  Properties of the U3 and 197 Model Comil
Parameter U3
Impeller Diameter (mm) 57
Min Impeller Speed (RPM) 2200
Min Tip Speed (m/s) 6.6
Max Impeller Speed (RPM) 7200
Max Tip Speed (m/s) 21.5
Screen Surface Area (­ cm2) 42.7
Screen Volume ­(cm3) 44.5
Screen volume/surface area ratio (cm) 1.04
mH
tm = (1)
ṁ
Mass throughput was determined using the procedure
detailed in Section 2.4. The mass hold-up for the U3 was
measured by blocking the screen to prevent discharge and
allowing the feed hopper to discharge into the impeller
zone. After the impeller speed reached the pre-determined
speed, the outlet of the hopper which sits on directly top
of the impeller zone was blocked and the impeller was
stopped. The material remaining in the impeller zone (i.e.
the mass hold-up) was measured three times and the aver-
age was reported. It should be noted that the mass hold-up
at steady-state should only depend on impeller speed and
not on screen properties provided that the discharge rate
of the feed hopper is higher than the discharge rate of the
comill which is true in this study resulting in a “chok-
ing” feed condition. Due to the choking feed condition, the
hold-up can be accurately measured by blocking discharge
from the screen while keeping all other experimental con-
ditions consistent with normal operation.
Flowability Analysis
The flowability of powder samples was evaluated using a
Shulze ring shear tester (RST-XS, Dietmar Shulze, Ger-
many). While a more detailed description of the shear test
can be found elsewhere [27], the following experimental
details are provided. A ring shear cell with a height of 13
mm, inner diameter of 32 mm, and outer diameter of 64
mm was used. The powder contained within the cell was
sheared using a lid with 16 equally spaced vanes 3 mm in
197
height. A pre-consolidation stress (i.e. normal stress at
111 pre-shear) of 1 kPa was used. The samples were sheared
1350 to failure under normal stresses of 250, 500, and 800 Pa
7.8 to obtain the yield locus. From the yield locus, the flow
4950 function coefficient (ffc) was obtained which is defined as
29.1 the ratio of the consolidation stress (major principle stress)
173 to the unconfined yield strength. The test was performed
320 in duplicate and the average was reported.
1.85

13
3178
Bulk Density Analysis
Bulk density was measured by gently pouring a powder
sample into a 100 ml graduated cylinder without causing
consolidation to a fill target of approximately 90 ml. The
mass and volume of the sample was measured, and the bulk
density was calculated (ρb = mass of sample/volume of sam-
ple). The test was performed in triplicate. As the test was
highly reproducible, error bars are not shown for any data.
Results and Discussion
Flowability Enhancement of Avicel PH 105 Using
Various Processing Methods
Avicel PH 105 is a fine grade of microcrystalline cellulose
with a median particle size of 20 μm. Due to its small parti-
cle size, Avicel PH 105 is considered cohesive and has poor
flowability. While Avicel PH 105 is not typically used in
capsule and tablet formulation due to its poor flowability, it
is used in this study as a model cohesive powder. In this sec-
tion, the improvement in flowability of Avicel PH 105 after
adding the pharmaceutical glidant, Aerosil R972, using a bin
blender, comill, or a LabRAM is investigated.
Figure 4 shows the flow function coefficient of Avicel PH
105 as-received and after incorporating 1% Aerosil R972
by various processing methods. A reference line is included
for the flow function coefficient of Avicel PH 102 (ffc =
4.8), a direct compression grade of microcrystalline cellu-
lose, which may be regarded as the minimum flowability
necessary for high speed tableting [28]. This value is only
8
Flow Function Coefficient, ffc (-)
7 enhancement provided by the lab-scale model U3 Comil.
6
Minium flowability
required for tabletting
5 model. Three 1397 μm round hole screens are investigated
4
3 with lower open area were custom fabricated. The design
2 and dimensions are identical to that of the Quadro screen
1
0 open area (see Fig. 2).
As Bin Co
-Re
cei Ble
ve d nd er
Fig. 4.  Pharmaceutical Research Special Issue: Pharmaceutical Par-
ticle and Crystal Engineering. Flow function coefficients for Avicel
PH 105 processed with 1% R972 using various methods. Comilling
conditions: 1397 μm round hole screen, square-shaped impeller, 7200
RPM impeller speed.
13
Pharmaceutical Research (2022) 39:3175–3184
intended to provide perspective and practical significance to
the flow function coefficient values discussed in the follow-
ing. As shown in Fig. 4, an enhancement in flowability (ffc
= 4.1) after bin blending is achieved in comparison to the
as-received material (ffc = 2.2). Yet, this improvement is still
less than what is required for tabletting. A slight improve-
ment is achieved by the comill (ffc = 4.7) in comparison
to bin blending and likewise fails to achieve the minimum
flowability needed for tabletting. A second (ffc = 5.1) and
a third pass (ffc = 5.4) through the comill provide further
improvement in the flowability of Avicel PH 105 which now
meets the minimum flowability requirement. The LabRAM,
regarded as a very effective dry-powder blender for incor-
porating glidants with cohesive powders [29], results in the
best enhancement in flowability (ffc = 7.0). For practical
purposes, this may be regarded as the highest flowability
that can be achieved by a dry powder blending process [29].
In comparison to the LabRAM, the poor effectiveness of bin
blending is apparent and better flowability can potentially
be achieved than what is attained by typical pharmaceuti-
cal manufacturing. The inadequacy of the comill, even after
three passes, is also evident in comparison to the LabRAM.
The poor effectiveness of the comill is attributed to the short
residence time of the process [26]. While additional passes
increase the total residence time and may further improve
the flowability, two passes through the comill would be
undesired in a manufacturing setting and may be regarded
as impractical. Though due to the promising ability of the
comill to enhance flowability, it is investigated more thor-
oughly in the next section.
Flowability Enhancement by Comilling: Lab Scale
Studies
This section evaluates the bulk density and flowability
Five impeller speeds are investigated from 2200-7200 RPM
which span the minimum and maximum allowable by this
whose open area are shown in Table 2. The manufacturer
screen is provided by Quadro while two additional screens
except that the holes in the top 75% or 90%, as measured by
the side length of the screen, were removed to reduce the
Co Co L ab
mil
l-1
mil
l-2
mil
l-3 RA The flow function coefficients for Avicel PH 105 after
st P nd rd P M comilling with 1% R972 using each screen and impeller
as s Pa as s
ss
speed are shown in Fig. 5. Reference lines are included for
the flow function coefficient of the as-received material
as well as the flow function coefficients after bin blending
and LabRAM processing. It is reiterated that the feed into
the comill is the same material prepared by bin-blending.
Pharmaceutical Research (2022) 39:3175–3184 3179

8 0.44
Comil U3 Manufacturer Screen Comil U3
Flow Function Coefficient, ffc (-)
75% Blocked Screen
7 LabRAM 90% Blocked Screen
Manufacturer Screen 0.42 LabRAM

Bulk Density, ρb (g/ml)

6 75% Blocked Screen
90% Blocked Screen

5 0.40
Bin Blender Bin Blender
4
0.38
3
As-Received
2 0.36

1 As-Received

0.34
0 2200 3450 4700 5950 7200
2200 3450 4700 5950 7200
Impeller Speed (RPM)
Impeller Speed (RPM)
Fig. 6.  Pharmaceutical Research Special Issue: Pharmaceutical Par-
Fig. 5.  Pharmaceutical Research Special Issue: Pharmaceutical Par- ticle and Crystal Engineering. Bulk Density for Avicel PH 105 pro-
ticle and Crystal Engineering. Flow function coefficients for Avicel cessed with 1% R972 using the U3 Comil with various screens and at
PH 105 processed with 1% R972 using the U3 Comil with various various impeller speeds.
screens and at various impeller speeds.

80
Comil U3
Accordingly, improvement provided by the comill should be Manufacturer Screen
70 75% Blocked Screen
compared against the flowability of the blend prepared by 90% Blocked Screen

bin-blending. Results show that increasing impeller speed Mass Throughput (g/s) 60
results in higher flow function coefficients. It is inferred that 50
higher impeller speed causes better deagglomeration, dis-
persion, and coating of the glidant resulting in lower inter- 40
particle cohesiveness and better flowability. Comilling with 30
the manufacturer’s screen results in minimal flowability
20
enhancement compared to bin blending even at the high-
est impeller speed. The modified screens with reduced open 10
area increase the effectiveness of comilling. Flowability
0
enhancement of the comill using the 90% blocked screen 2200 3450 4700 5950 7200
at 7200 RPM approaches the effectiveness of the LabRAM
Impeller Speed (RPM)
which for practical purposes is considered the best possible
flowability achievable. The similar effectiveness between the Fig. 7.  Pharmaceutical Research Special Issue: Pharmaceutical Par-
ticle and Crystal Engineering. Mass throughput for Avicel PH 105
LabRAM and the comill with the modified screen is notable processed with 1% R972 using the U3 Comil with various screens
considering the former is a batch process and the latter is a and at various impeller speeds.
continuous process. The corresponding bulk densities are
shown in Fig. 6. Observations for bulk density and flowabil-
ity are equivalent and discussion will not be repeated here. Table 3.  Mass Hold-Up for the Comil Impel- Mass
To further understand the effect of screen open area and U3 Comil at Various Impeller ler Speed Hold-up
Speeds
impeller speed on flowability enhancement, the mean resi- (RPM) (g)
dence time was calculated by measuring the mass through-
U3 2200 16.5
put and mass hold-up. Figure 7 shows the mass throughput
3450 14.2
for each screen and impeller speed. Increasing impeller
4700 11.5
speed results in higher throughput since the impeller is
5950 10.1
responsible for pushing material through the screen. The
7200 8.5
modified screens with lower open area also result in lower
throughput as intuitively expected. Based on the through-
put and the mass hold-up specified in Table 3, the mean
residence time was calculated and shown in Fig. 8. Results beneficial for deagglomeration, dispersion, and coating of
show that increasing impeller speed decreases the mean resi- the glidant and results in overall better process effectiveness
dence time in agreement with previous work [30]. While despite the decrease in the mean residence time. The low
mean residence time may be expected to positively corre- open area of the modified screens, as intuitively expected,
late with flowability enhancement, higher impeller speed is increase the mean residence time at each impeller speed

13
3180 Pharmaceutical Research (2022) 39:3175–3184

1.0 The results of this section show that an effective dry-

Comil U3
0.9 Manufacturer Screen
coating processes for the purpose of flowability and bulk
Mean Residence Time, tm (s)

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
2200 3450 4700
Impeller Speed (RPM)
Fig. 8.  Pharmaceutical Research Special Issue: Pharmaceutical
Particle and Crystal Engineering. Mean Residence time for Avicel
PH 105 processed with 1% R972 using the U3 Comil with various
screens and at various impeller speeds.
in comparison to the manufacturer’s screen and improves
the effectiveness of the process. The 90% blocked screen is
shown to increase mean residence time by a factor of 2.2 at
7200 RPM in comparison to the manufacturer screen. The
relationship between mean residence time and flow function
coefficient is shown in Fig. 9. High impeller speed com-
bined with the increased mean residence time provided by
modified screen results in the most effective process and
best flowability enhancement. Our previous study, using a
similar experimental set-up to evaluate the effect of screen
properties (open area and hole size), showed that flowability
enhancement was solely dependent on the mean residence
time. Since the effect of impeller speed was not previously
evaluated, this current study gives a more complete evalu-
ation of processing parameters on flowability enhancement
75% Blocked Screen density enhancement can be practically incorporated into
90% Blocked Screen
pharmaceutical manufacturing. Comilling is a ubiquitous
unit operation in the processing of tablets and capsules and
can easily be adopted and developed as a dry-coating pro-
cess. Fabrication of modified screens with reduced open area
represent a small investment but improve the effectiveness
of the process. While previous studies have recommended
multiple passes through the comill [21–25], the design of the
screens used here may be particularly beneficial. Figure 10
shows the data of Fig. 9 with linear fittings at each impeller
5950 7200 speed. Based on the data of Fig. 9, these lines give the flow
function coefficient one would attain at each impeller speed
if the mean residence could be independently controlled.
However, if the multi-pass method is used with the manufac-
turer’s screen, the process is less effective than expected as
shown by the data points in Fig. 10. This may be due to fact
that the modified screens force the material to be discharged
at the bottom after passing through the impeller zone. The
manufacturer’s screen may result in a portion of the material
quickly discharging at the top of the screen without being
dry-coated. Residence time distribution studies may confirm
this hypothesis. While the exact cause of this discrepancy
is not determined here, the benefit of the modified screen
used in place of a multi-pass approach is readily apparent.
The use of the modified screens both improves the effective-
ness of the comill process and avoids manufacturing inef-
ficiencies associated the multi-pass approach. These factors
result in a more practical process and may lead to a wider
7.0 Manufacturer Screen
7200 RPM
7200 RPM:
Flow Function Coefficient, ffc (-)

using the modified screens. 6.5 5950 RPM

1st Pass
2nd Pass
3rd Pass
6.0 4700 RPM
d
cte

7.0
pe

Comil U3 5.5
Ex
Flow Function Coefficient, ffc (-)

6.5 Manufacturer Screen 3450 RPM

75% Blocked Screen
5.0
6.0 90% Blocked Screen
tu al 2200 RPM
Ac
5.5 4.5

5.0 4.0

4.5 3.5
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
4.0
Mean Residence Time, tm (s)
Higher impeller speed
3.5
Fig. 10.  Pharmaceutical Research Special Issue: Pharmaceutical
3.0 Particle and Crystal Engineering. Relationship between flow func-
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 tion coefficient and mean Residence time for Avicel PH 105 pro-
Mean Residence Time, tm (s) cessed with 1% R972 using the U3 Comil with various screens and
at various impeller speeds. Linear fittings are shown at each impeller
Fig. 9.  Pharmaceutical Research Special Issue: Pharmaceutical Par- speed. Data points are shown for the 1­ st, ­2nd, and ­3rd pass through the
ticle and Crystal Engineering. Relationship between flow function comill using the manufacturer screen and an impeller speed of 7200
coefficient and mean Residence time for Avicel PH 105 RPM.

13
Pharmaceutical Research (2022) 39:3175–3184 3181

acceptance and incorporation of dry-coating into pharma- 8

Comil 197
ceutical manufacturing.

Flow Function Coefficient, ffc (-)

7 LabRAM
Manufacturer Screen
75% Blocked Screen
6 90% Blocked Screen

5
Flowability Enhancement by Comilling:
Bin Blender
Manufacturing Scale Studies 4

3
This section evaluates the effectiveness of comilling using a 2
As-Received

manufacturing scale 197 model Comil. While this is Quad-

1
ro’s smallest “overdriven” Comil, it has a stated capacity
0
of over 300 kg/hr for size reduction processing and can be
1850 3700 4950
used for pilot-scale or commercial manufacturing. Com-
Impeller Speed (RPM)
parison of the 197 and the U3 is provided in Table 1. While
Fig. 11.  Pharmaceutical Research Special Issue: Pharmaceutical
the impeller and screen diameter of the 197 is larger than
Particle and Crystal Engineering. Flow function coefficients for Avi-
the U3, the volume to surface area ratio of the screen and cel PH 105 processed with 1% R972 using the 197 Comil with vari-
impeller zone may be particularly important to note. With a ous screens and at various impeller speeds.
larger volume to surface area ratio, one may expect higher
mean residence time and better mixing potentially result-
ing in higher effectiveness at larger scale. The 197 can also 0.44
Manufacturer Screen Comil 197
achieve significantly higher impeller tip speeds (29.1 m/s) 75% Blocked Screen
90% Blocked Screen
than the U3 (21.5 m/s) in which to shear the material in the Bulk Density, ρb (g/ml)
0.42 LabRAM

impeller zone.
As was investigated for the U3, three 1397 μm round hole
screens are evaluated for the 197. The manufacturer screen
is provided by Quadro while two additional screens with
lower open area were custom fabricated by removing the
holes at the top 75% or 90%, as measured by the side length
of the screen (see Fig. 2). The open area of these screens
is detailed in Table 2. Only a slight difference between the
open areas of the U3 and 197 screens is noted. Three impel-
ler speeds were investigated: 4950 RPM is the maximum
impeller speed of the 197, 3700 RPM is equivalent to the tip
speed of the U3 at maximum impeller speed (7200 RPM),
and 1850 RPM is equivalent to 50% the maximum tip speed
of the U3.
The flow function coefficients for Avicel PH 105 after
comilling with 1% R972 using each screen and impeller
speed are shown in Fig. 11. As observed previously for the
U3, higher impeller speed and screens with lower open area
results in more effective processing. Once again, the manu-
facturer’s screen results in minimal flowability enhancement
while the modified screens result in a more effective pro-
cess. Flowability enhancement of the 197 using the 90%
blocked screen at 4950 RPM surpasses the highest effec-
tiveness of the U3 and fully achieves the effectiveness of
the LabRAM (i.e. best possible flowability). It’s noted that
the 197 at 4950 RPM has a significantly higher impeller tip
speed (29.1 m/s) than the U3 at 7200 RPM (21.5 m/s). The
equivalent flowability enhancement obtained between the
197 and the LabRAM is again a noteworthy achievement and
demonstrates a substantial improvement in process effective-
ness provided by the modified screens. The corresponding
bulk densities are shown in Fig. 12. Observations for bulk
0.40
Bin Blender
0.38
0.36
As-Received
0.34
1850 3700 4950
Impeller Speed (RPM)
Fig. 12.  Pharmaceutical Research Special Issue: Pharmaceutical
Particle and Crystal Engineering. Bulk Density for Avicel PH 105
processed with 1% R972 using the 197 Comil with various screens
and at various impeller speeds.
density and flowability are equivalent and discussion will
not be repeated here.
Mass throughput was also measured for the 197 as
shown in Fig. 13. As observed previously, the throughput is
increased at higher impeller speed and reduced by the low
open area of the modified screens. The 90% blocked screen
is shown to decrease mass throughput by a factor of 2.6 at
4950 RPM in comparison to the manufacturer screen. This
corresponds to an increase in the mean residence time of 2.6
since mass-hold up only depends on impeller speed in this
experimental set-up. Unlike the U3, the mass hold-up in the
impeller zone could not be measured due to the technical
challenges presented by the design of the 197. The 197 has a
transfer chute connecting the feed bin and the impeller zone
as well as a top-driven impeller which make direct or indi-
rect measurement of the hold-up experimentally difficult.
Accordingly, an accurate hold-up could not be obtained to
calculate the mean residence time of the 197.

13
3182 Pharmaceutical Research (2022) 39:3175–3184

200 calculated based on the mean residence time and the impel-
Comil 197
180
Manufacturer Screen
75% Blocked Screen
ler tip speed (vTip).
90% Blocked Screen
160
Mass Throughput (g/s)

140
120
100
80
60
40
20
0 scale-up parameter, this study has still successfully shown
1850 3700
Impeller Speed (RPM)
Fig. 13.  Pharmaceutical Research Special Issue: Pharmaceuti-
cal Particle and Crystal Engineering. Mass throughput for Avicel
PH 105 processed with 1% R972 using the 197 Comil with various
screens and at various impeller speeds.
Due to the inability to obtain the mean residence time, an
important comparison between the two scales could not be
established. However, comparison of the flow function coef-
ficients obtained at 7200 RPM for the U3 and 3700 RPM for
the 197 in Fig. 14 shows that the two comills have similar
effectiveness. At these impeller speeds, both comills have
an impeller tip speed of 21.5 m/s. The data suggests that
the extent of flowability enhancement will be similar at dif-
ferent scales if screen open area and impeller tip speed are
kept constant. To evaluate a method of scaling the process,
the mean travel distance was also calculated for the U3. The
mean travel distance, as shown in Eq. (2), was previously
used by Toson et al. [31] to evaluate a continuous powder
mixer with a design similar to the comill. Here, the mean
travel distance of the powder within the impeller zone is
dm = tm vTip (2)
The mean travel distance obtained for the U3 is shown in
Fig. 15. While it is expected to positively correlate with the
flow function coefficient, this is not the case. In this attempt
to resolve both mean residence time and impeller speed, a
parameter that can be used for scale-up of this process is
still unknown. In absence of residence time data or a useful
4950
that an effective dry-coating process can be developed at the
larger scale using the modified screens. Regardless, scale-up
should be straightforward as the effects of impeller speed
and screen open area are apparent and should be consist-
ent at lab and manufacturing scale. Accordingly, a scalable
and effective dry-coating process using the comill is shown
here which can be readily adopted by the pharmaceutical
industry. The use of comill dry-coating can mainly serve as
a process to improve the bulk properties of fine materials.
This may include fine excipients as shown here which can
have advantages in tablet manufacturing compared to coarse
excipients [26, 32]. The process can also be applied to fine
active pharmaceutical ingredients which often exhibit poor
flow properties [26]. While the comill was exhibited as a
batch process in this study, the use of the modified screens
may be useful in continuous manufacturing. Although for
continuous manufacturing, the comill discharge rate may
controlled independently of the screen properties either
by the throughput of downstream unit operations or by the
incorporation of discharge valves as shown by Toson et al.
[31] for a continuous powder mixing process. The main
advantage of the modified screens used in this study is that

7 7.0
v Tip = 21.5 m/s Manufacturer Screen Comil U3
Flow Function Coefficient, ffc (-)

Flow Function Coefficient, ffc (-)

Comil U3 (7200 RPM) 6.5 75% Blocked Screen

6 Comil 197 (3700 RPM) 90% Blocked Screen

6.0
5
5.5
4
5.0
3 4.5

2 4.0

1 3.5

3.0
0 2.0 3.0 4.0 5.0 6.0 7.0
Manufacturer Screen 75% Blocked Screen 90% Blocked Screen
Mean Travel Distance, dm (m)
Fig. 14.  Pharmaceutical Research Special Issue: Pharmaceutical
Particle and Crystal Engineering. Comparison of flow function coef- Fig. 15.  Pharmaceutical Research Special Issue: Pharmaceutical
ficients obtained by the U3 and 197 at equivalent tip speeds (21.5 Particle and Crystal Engineering. Relationship between flow func-
m/s) using various screens. tion coefficient and mean travel distance for the U3.

13
Pharmaceutical Research (2022) 39:3175–3184
no changes to typical operation of the comill (batch or con-
tinuous) and no modification of the comill itself is required.
Conclusions
The effectiveness of the comill as a dry-coating process
was improved by the use of modified screens with reduced
open area. The modified screens were shown to increase the
mean residence time and to improve the extent of flowability
and bulk density enhancement for the lab scale Comil U3.
In comparison to the “multi-pass” approach, the modified
screens offer a superior improvement to the process. The
modified screens were also shown to improve the effective-
ness of the manufacturing scale model Comil 197. While
the mean residence time of the 197 could not be determined,
results show that the process is scalable and that flowability
and bulk density enhancement equivalent to the LabRAM,
a batch dry-coating process, can be achieved. Overall, this
study shows that the comill can readily be used as a prac-
tical and effective dry-coating process for pharmaceutical
manufacturing.
Funding Research reported in this publication was funded by AbbVie.
The authors have no conflicts of interest to declare.
Disclosure
AbbVie funded and participated in the study design, research, data col-
lection, analysis and interpretation of data, as well as writing, review-
ing, and approving the publication. Maxx Capece, and Jeffery Larson
are AbbVie employees and may own AbbVie stock/options.
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